Necrosis inhibitors

#Tumor necrosis factor alpha (TNF-α)-induced NF-κB activation plays a central role in the immune system and inflammatory responses. Receptor-interacting protein 1 (RIP1) is a multi-functional signal transducer involved in mediating nuclear factor κB (NF-κB) activation, apoptosis, and necroptosis. The kinase activity of RIP1 is critically involved in mediating necroptosis, a caspase-independent pathway of necrotic cell death. Holler et al. Nat Immunol 2000; 1: 489-495; Degterev et al. Nat Chem Biol 2008; 4: 313-321.

#Necroptosis plays a role in various pathological forms of cell death, including ischemic brain injury, neurodegenerative diseases and viral infections. Dunai, et al., December 2011, Pathol. Oncol. Res.: POR 17 (4): 791-800. Necrostatin-1 (Nec-1), a small molecule inhibitor of RIP1 kinase activity, can block necroptosis. Degterev et al. Nat Chem Biol 2005; 1: 112-119.

#Related patent publications include: U.S. Pat. No. 6,756,394, U.S. Pat. No. 8,278,344, US2012122889, US2009099242, US2010317701, US2011144169, US20030083386, US20120309795, WO2009023272, WO2010075290, WO2010075561, WO2012125544.

#TABLE 1 Compound List 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 S1 S2 S3 S4 S5 S6 S7 S8 S9 S10 S11 S12 S13 S14 S15 S16 S17

#2-phenylaziridine (35 mg, 0.294 mmoL) and triethylamine (59.4 mg, 0.588 mmol) were dissolved in 1.5 mL of dry CH2Cl2. 2,2-dimethylbutanoyl chloride (43.3 mg, 0.323m mol) in 1 mL of CH2Cl2 was added slowly to the solution at 0° C. under nitrogen. The mixture was stirred at room temperature for 2 h, diluted with CH2Cl2 and water. The organic layer were washed with saturated NaHCO3, brine, dried with Na2SO4 and concentrated. The residue was purified by chromatography to give compound 1 (20 mg, 31%) as an colorless oil 1HNMR(CDCl3, 400 MHz): δ7.36-7.44 (m, 5H), 5.90 (dd, 1H, J=9.2, 4.0 Hz), 3.44 (dd, 1H, J=13.6, 9.2 Hz), 3.26 (dd, 1H, J=4.0, 13.6 Hz), 1.61 (qd, 2H, J=7.6, 2.4 Hz), 1.21 (s, 3H), 1.19 (s, 3H), 0.74 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H]+ calad for C14H19NO, 218.1; found, 218.3.

#The titled compound 2 was prepared in 77% yield from 2-phenylazetidine (50 mg) and 2,2-dimethylbutanoyl chloride (55 mg) according to the procedure outlined for compound 1. 1HNMR(CDCl3, 400 MHz): δ 7.31-7.36 (m, 4H), 7.23-7.28 (m, 1H), 5.35-5.39 (m, 1H), 4.34-4.46 (m, 2H), 2.66-2.74 (m, 1H), 2.07-2.14 (m, 1H), 1.59 (q, 2H, J=7.6 Hz), 1.14 (s, 6H), 0.89 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H]+ calad for C15H21NO, 232.2; found, 232.4.